Cocaine abuse continues to be a significant public health problem. In spite of increased scientific investigation, the brain mechanisms responsible for compulsive cocaine use are still not clearly defined. The basic brain processes underlying compulsive cocaine use involve complex neuronal circuits and networks. Project five proposes continued investigation of these brain processes using a rat intravenous self- administration model. A recently completed turnover rate study in cocaine self-administering rats has suggested dopamine (DA), norepinephrine, serotonin, aspartate, glutamate and GABA releasing neurons in discrete brain regions to be important to the processes maintaining these behaviors. Experiments are proposed to use microdialysis and neurotoxin induced lesions to evaluate the involvement of and potential interrelationships between DA innervations of the ventral pallidum (VP) and nucleus accumbens (NA) in cocaine self-administration. In addition, the involvement of DA innervations of the NA and VP in the self- administration of cocaine-heroin combinations (speed ball) will be investigated using similar procedures. Another series of experiments will assess the effects of novel tropanes that attenuate cocaine self- administration on speed-ball administration to determine if these long acting and potent compounds also alter this intake. The overall goal of the proposed research for the next funding period is to further characterize the brain processes underlying compulsive use of cocaine and speed ball.